delta4, 9(11)-pregnadienes



United States Patent A -PREGNADIENES Seymour Bernstein, Pearl River, N. Y., and Robert H. Lenhard, Ridgefield Park, N. J., assiguors to American Cyanamid Company, New York, N. Y., a corporation of Maine No Drawing. Application December 3, 1956 Serial No. 625,606

6 Claims. (Cl. 260-39745) onto R 0:0

in which R is hydrogen or a lower alkanoyl radical and R is a lower alkanoyl radical.

The present application is a continuation-in-part of our copending application, Serial No. 519,248, filed June 30, 1955, now Patent No. 2,773,058.

The compounds of the present invention are relatively high melting crystalline solids. They are soluble in the common organic solvents and relatively insoluble in water.

The compounds of the present invention are prepared from a 2l-lower alkanoic acid ester of A pregnatriene-2l-ol-3,20-dione, which is treated with osmium tetroxide in an organic solvent, such as benzene, xylene, toluene, etc., in the presence of a tertiary amine, such as pyridine. The corresponding osmate ester is formed, which ester is then decomposed by water and an organic solvent under alkaline conditions. The organic solvent can be those mentioned above and the alkaline conditions can be produced by the addition of potassium bicarbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, etc. to the reaction mixture. The product obtained is a 21-lower alkanoic acid ester of A -pregnadiene-16a,17ot,2l-triol-3,20-dione. The latter product when treated with a lower alkanoic acid anhydride produces a l6a,21-di-lower alkanoic acid ester of A -pregnadiene-16a,l7ot,2l-triol-3,20-dione.

The present compounds are useful as intermediates in the preparation of the compounds described in our copending application, Serial No. 519,248, filed June 30, 1955. Furthermore, the compounds described in the latter application are convertible to steroids having high physiological activity. This activity reaches, and in many instances exceeds, that of cortisone and hydrocortisone without the undesirable side elfects.

The following examples describe in detail the preparation of A -pregnadiene-3,20-diones of the present invention:

Example 1 A solution of 0.70 g. of A -pregnatriene-21-ol- 3,20-dione 21-acetate and 0.50 g. of osmium tetroxide in ml. of benzene and 0.5 ml. of pyridine was allowed to stand at room temperature for 18 hours. The osmate a ICC ester was decomposed by the addition of 35 ml. of water, 10 ml. of benzene, 23 ml. of methanol and 3.58 g. each of sodium sulfite and potassium bicarbonate. After stirring the mixture for 5 hours, approximately ml. of chloroform was added and the stirring continued for /2 hour. The mixture was filtered through diatomaceous earth, the residue washed with hot chloroform and the organic layer separated. The aqueous phase was extracted several times with chloroform and the combined extracts were washed with saturated saline and with water. The dried extract was evaporated under reduced pressure and the residue crystallized from acetonepetroleum ether to give 0.62 g. of crude product, melting point l72-l74 with previous softening. Three recrystallizations from acetone-petroleum ether gave 0.42 g. of pure A -pregnadiene-16a,17a,2l-triol-3,20-dione 2l-acetate, melting point 197.5 with previous softening. One additional recrystallization did not alter the melting point;

u... ale. 3 5 m 16,700) -|-93 (chloroform) max.

Analysis.Calcd. for (3231 13006: C, H, 7.51. Found: C, 68.72; H, 7.79.

Example 2 Analysis.Calcd. for C25H32O7I C, 67.55; H, 7.26. Found: C, 67.31;H, 7.49.

Example 3 27.0 g. of A -pregnatriene-Z1-ol-3,20-dione 21 acetate was dissolved in 800 ml. of benzene and 15 ml. of pyridine. The osmium tetroxide (20 g.) in 300 ml. of benzene was added with stirring to. the steroid mixture over the course of about /2 hour. Stirring was continued for several hours and the mixture allowed to stand over night. To the mixture was added 950 ml. of methanol followed by a solution of 135 g. sodium sulfite and 135 g. of potassium bicarbonate in 1400 ml. of water and the mixture allowed to stir for 7-8 hours. About 1 liter of chloroform was added and the mixture stirred for an additional hour and then allowed to stand over night. The reaction mixture was filtered through a sintered glass funnel, the organic layer separated and the aqueous layer extracted 4-5 times with chloroform. The filter cake was extracted several times with hot chloroform, all organic extracts combined, washed twice with water and dried over magnesium sulfate-activated charcoal. After filtration, it was evaporated to dryness under reduced pressure and the residue crystallized from acetone to yield 15.2 g. (gray solid) of A -pregnadiene-16a,17m,21-triol-3,20-dione 21-acetate.

Example 4 To 15.5 g. of .A -pregnadiene-16a,17a,21-triol- 3,20-dione 21 acetate in 550 ml. of pyridine was added 18 ml. of acetic anhydride and the mixture allowed to stand overnight. Methanol was added and the solution evaporated to dryness under reduced pressure. Crystallization of the residue from acetone-petroleum ether (B. P. 6070) gave 15.4 g. of A -pregnadiene- 16oz,17a,21-t1i01-3,20-di0n6 16a,2l-diacetate, melting point tained by the addition of water and an organic solvent under alkaline conditions, and recovering a 21-lower alkanoic acid ester of A -pregnadiene-16a,l7a,21-

We claim: triol-3,20-dione therefrom. 1. Compounds having the general formula 5 5. A process which comprises reacting A -pregnatriene-Z1-ol-3,20-dione 21-acetate with osmium tetroxide in the presence of benzene and pyridine, decomposing the osmate ester so obtained by the addition of water ----OH and an orgamc solvent under alkaline conditions and R 10 recovering A -pregnadiene-16a,l7a,21-triol-3,20-dione 2l-acetate therefrom.

6. A process which comprises reacting A -pregnatriene-21-ol-3,20-dione 21-acetate with osmium tetroxide in the presence of benzene and pyridine, decomposing 15 the osmate ester so obtained by the addition of water and an organic solvent under alkaline conditions, treating the reaction product with acetic anhydride and recover-ing A -pregnadiene-16a,17a,2l-triol-3,20-dione 16a, 2 l -diacetate therefrom.

ozl

in which R is a member of the group consisting of hydrogen and lower alkanoyl radicals and R is a lower alkanoyl radical.

2. The compound A -pregnadiene-16u,17a,21-triol- 2O 3,20-dione 21-acetate.

3. The compound A -pregnadiene-16a,17a,21-triol- 3,20dione 16a,21-diacetate.

References Cited in the file of this patent UNITED STATES PATENTS 4. A process which comprises reacting a 21-lower 2,756,179 Fried et a1. July 24, 1956 alkanoic acid ester of A -pregnatriene-Z1-ol-3,20- 25 2,773,053 Bernstein et a1 1956 dione with osmium tetroxide in an organic solvent and 2,733,030 Bernstein et aL 1956 a tertiary amine, decomposing the osmate ester so ob- 

1. COMPOUNDS HAVING THE GENERAL FORMULA 